Wu Xian, Song Mingyue, Wang Minqi, Zheng Jinkai, Gao Zili, Xu Fei, Zhang Guodong, Xiao Hang
Department of Food Science, University of Massachusetts, Amherst, MA, USA.
Institute of Agro-Products Processing Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, P. R. China.
Mol Nutr Food Res. 2015 Dec;59(12):2383-94. doi: 10.1002/mnfr.201500378. Epub 2015 Oct 7.
Nobiletin (NBT) is a major citrus flavonoid with various health benefits. Herein, we investigated the colon cancer chemopreventive effects of NBT and its colonic metabolites in a colitis-associated colon carcinogenesis mouse model as well as in human colon cancer cell models.
In azoxymethane/dextran sulfate sodium treated mice, oral administration of NBT effectively decreased both incidence and multiplicity of colonic tumors. NBT showed significant antiproliferative, proapoptotic, and anti-inflammatory effects in the mouse colon. HPLC analysis revealed that oral administration of NBT resulted in high levels of metabolites, i.e. 3'-demethylnobiletin (M1), 4'-demethylnobiletin (M2), and 3',4'-didemethylnobiletin (M3) in the colonic mucosa. In contrast, the colonic level of NBT was about 20-fold lower than the total colonic level of three metabolites. Cell culture studies demonstrated that the colonic metabolites of NBT significantly inhibited the growth of human colon cancer cells, caused cell-cycle arrest, induced apoptosis, and profoundly modulated signaling proteins related with cell proliferation and cell death. All of these effects were much stronger than those produced by NBT alone.
Our results demonstrated that oral administration of NBT significantly inhibited colitis-associated colon carcinogenesis in mice, and this chemopreventive effect was strongly associated with its colonic metabolites.
川陈皮素（NBT）是一种主要的柑橘类黄酮，具有多种健康益处。在此，我们在结肠炎相关结肠癌发生小鼠模型以及人结肠癌细胞模型中研究了NBT及其结肠代谢产物的结肠癌化学预防作用。
在给予氧化偶氮甲烷/葡聚糖硫酸钠处理的小鼠中，口服NBT可有效降低结肠肿瘤的发生率和多发性。NBT在小鼠结肠中显示出显著的抗增殖、促凋亡和抗炎作用。高效液相色谱分析显示，口服NBT导致结肠黏膜中代谢产物水平升高，即3'-去甲基川陈皮素（M1）、4'-去甲基川陈皮素（M2）和3'，4'-二去甲基川陈皮素（M3）。相比之下，NBT的结肠水平比三种代谢产物的总结肠水平低约20倍。细胞培养研究表明，NBT的结肠代谢产物显著抑制人结肠癌细胞的生长，导致细胞周期停滞，诱导凋亡，并深刻调节与细胞增殖和细胞死亡相关的信号蛋白。所有这些作用都比单独使用NBT产生的作用强得多。
我们的结果表明，口服NBT可显著抑制小鼠结肠炎相关的结肠癌发生，且这种化学预防作用与其结肠代谢产物密切相关。
